Thomas Kramer, MD


Medscape General Medicine. 2002;4(4) 


Psychopharmacology is, at its best, a field of increasing possibilities. New agents and new uses for existing agents provide us with new ways to help our patients have better lives. What we have to offer seems to grow exponentially. There are a number of reasons for this delightful explosion. We have just concluded the "Decade of the Brain," marking renewed interest and success in neuroscience research. A somewhat more cynical view is that the pharmaceutical industry has figured out that there is enormous money to be made developing psychotropics, and is increasing energy and expenditures in our direction. The sales that they have generated, regardless of the underlying motivation, reflect the prevalence of behavioral disorders and the continued need for better treatments.

These new possibilities can be sorted into 3 basic categories: new agents, new preparations of existing agents, and new uses for existing agents. The last category can be subdivided into two: approved and unapproved by the US Food and Drug Administration. The big difference between the last two is that the pharmaceutical industry is only allowed to market the former, so practitioners will hear a great deal more about those, but they may end up discovering some of the latter.

The other reality of drug development coming from a for-profit industry is that successful agents will spawn "me too" agents from competitors. The compounds may have little or no advantage over their predecessors, but are developed solely to get a share of a lucrative market. They may be presented as new, and may have some useful distinctions, but at best represent a refinement rather than a truly new agent. Two examples of agents that I would consider to be really new are aripiprazole and atomoxetine. Aripiprazole was the subject of a previous column, and will surely be the first of many "dopamine system stabilizers." It represents an important new pharmacologic treatment for at least schizophrenia and perhaps other psychotic disorders. Atomoxetine is the first selective noradrenergic reuptake inhibiter (SNRI) available in this country. Reboxetine is an SNRI that has been available in Europe for a while and seemed to be ready for approval here, but there have been problems with its clinical trials both with safety (some cases of hypertension) and efficacy (not enough positive data from domestic studies, as opposed to overseas) so the first SNRI that American practitioners will be able to prescribe will be atomoxetine.

There are quite a few agents that are currently being marketed as new drugs but, I think, have a great deal of resemblance to existing agents. Duloxetine, for example, is being presented as an important new antidepressant because it has dual action blocking the reuptake of both serotonin and norepinephrine. However, so does venlafaxine, which has been around for a number of years. If there is an advantage to duloxetine over venlafaxine, it is not clear in the data currently available. Ziprasidone is just one more in a long line of new generation antipsychotics, and there may be more; iloperidone may be marketed soon. They all have strengths and weaknesses, but are all of the same class.

Much attention has been paid recently to the process of drug development by separating out specific isomers of drugs from racemic mixtures. Examples of recent drugs developed in this way are the antidepressant escitalopram and the stimulant dexmethylphenidate. However, there is no evidence as far as I know that these new drugs are more effective or have any advantages over their parent racemic drugs. Moreover, there is nothing new about isomeric drug development. Levodopa and dextroamphetamine are products of this process and have been around for a while.

What has proven to be just as important as new agents are new preparations of existing agents. Risperidone injections that can be given once every 2 weeks will be available soon, and may represent a major advance for treatment of the severely mentally ill. There are multiple new long-acting preparations of existing stimulants that have dramatically improved the treatment of attention deficit/hyperactivity disorder (ADHD). Even Paxil CR, a longer acting version of paroxetine, has made a useful agent more tolerable.

A recent article in The New England Journal of Medicine[1] illustrates the importance of the discovery of new uses for existing agents. This study showed that miltefosine, a medication originally developed for treatment of cancer and found to be marginally effective, was remarkably effective in the treatment of visceral leishmaniasis, and as such is the only oral treatment for that disease. Psychopharmacology has and will have examples of new indications for existing agents that may be almost as dramatic. Much of psychopharmacology's history is based on this. For example, monoamine oxidase inhibitors were discovered when a treatment for tuberculosis serendipitously made depression better.

One of the most important psychopharmacology examples of new indications for existing agents is the discovery that agents originally developed for the treatment of seizures, particularly partial complex seizures, are very effective mood stabilizers. Psychiatrists currently use these drugs so most of us probably forget that they were first intended for neurologists. Most recently, modafinil, originally developed for narcolepsy, has been used successfully in mood disorders, ADHD, and, because of its low risk for abuse, as alternative adjunctive treatment for substance abusers. Mifepristone, also known as RU-486, is well known as a medical abortion agent, but small studies are showing robust efficacy in treatment-resistant and psychotic depression.

In another example that may be stretching the bounds of psychopharmacology, vagal nerve stimulation was developed as a treatment for intractable epilepsy, and consists of a device implanted in the patient that provides direct stimulation of the vagus nerve. Studies have shown this treatment to be very effective in treatment-resistant depression, and more recently in improving cognition in Alzheimer's disease.

The process of discovery of off-label uses of agents goes hand in hand with the development of new agents. One can take what has been learned previously and consider it with new and upcoming agents. For example, I am intrigued by the potential of the relatively new antiseizure medication levetiracetam as a mood stabilizer. I have not tried it yet clinically, but for patients who have trouble tolerating other mood stabilizers, this drug may have promise. Its side effect profile is so benign, and as an epilepsy drug, it performs so much like other drugs that are effective mood stabilizers, that it may have an important role. The problem is that its mechanism of action is unknown, so there is no way of knowing whether it would be effective. All that can be said now with reasonable certainty is that it is probably safe.

Even the truly new and exciting compounds mentioned at the beginning of this column will soon be examined for off-label use. Aripiprazole will be marked as a treatment for schizophrenia, but only time will tell if it will have a role in the treatment of other psychotic disorders such as bipolar disorder or substance-induced psychosis. It may even have some direct mood stabilizing properties, as olanzapine was found to have after it came to market. I would go so far as to guess that atomoxetine might be a very effective antidepressant and could be useful in the treatment of anxiety disorders such as generalized anxiety and panic disorder.

Finally, as we reflect on where these new possibilities come from, it is important to acknowledge our debt to our most difficult to treat patients. They are the ones who provide us with the opportunity to learn new things by trying what has not been tried before. Off-label uses are discovered when the on-label treatments do not work. In our quest to help our patients, we keep trying different things until we get the desired result, and we apply what we have learned to the next patient. It has been said that the bravest person who ever lived was the first person to eat an egg. Let us not forget the courage of the first patients who consented to the treatments we take for granted today.